Orally administerable sustained release pharmaceutical formulations

ABSTRACT

This invention provides orally administerable pharmaceutical formulations having a semi-solid matrix containing a hydrophilic substance capable of creating channels in a hydrophobic carrier matrix thereby providing a sustained rate of release of an active agent from the formulation.

This application is a division of application Ser. No. 797,305 filedNov. 12, 1985, now U.S. Pat. No. 4,797,286.

BACKGROUND OF THE INVENTION

Gelatin capsules are widely used in the pharmaceutical industry for oraladministration of a variety of active agents. In general, there are twotypes of gelatin capsules. Soft gelatin capsules are used to containsemisolids, liquids and pastes, and hard gelatin capsules are used tocontain powders and granules. Soft gelatin capsules suffer from thedisadvantages that they require significantly more gelatin forencapsulation of a given dose of pharmaceutically active compound thanhard gelatin capsules, and that they are typically made and filled bycontract manufacturers. Hard gelatin capsules are supplied by specialistmanufacturers for filling by the producer of the material to beencapsulated. Quality control considerations favor capsule filling bythe producer of the filling material and considerable increases in theprice of gelatin favor the use of hard gelatin capsules. However, ifhard gelatin capsules are used to contain materials other than powdersand granules, there have been problems of leaking of capsule contents inhandling. The leaking can only be overcome by time-consuming andcumbersome operations such as banding of the capsule after filling. Suchoperations add greatly to production costs.

Recently, a capsule filling medium which is semisolid, liquid orpaste-like in nature has been developed which can be readily introducedinto hard gelatin capsules without the expected problems of leakage.This thixotropic medium can be introduced into the capsule in a state oflow viscosity and, once in the capsule, the medium assumes a relativelyhigh viscosity, thereby reducing the tendency of the medium to leak fromthe capsule. These formulations are described in detail in U.K. Pat. No.1,590,864.

The use of semi-solid matrix formulations permits the control of therate of release of the active agent in the formulation by altering thehydrophilic-lipophilic balance of the matrix. Matrices of highlipophilicity having a high melting point erode slowly, thereby delayingthe release of the active agent from the matrix. In contrast, matricesthat are highly hydrophilic and have melting points at or near about 37°C. will dissolve rapidly.

The present invention provides a sustained release pharmaceuticalformulation in capsule unit dosage form comprising a gelatin capsulecontaining a semi-solid matrix comprising a pharmaceutically activeagent, a pharmaceutically acceptable hydrophobic carrier matrix and ahydrophilic substance capable of providing diffusion channels into thehydrophobic carrier. The present formulation contains a non-dispersing,slow eroding hydrophobic matrix having a melting point greater thanabout 37° C. The hydrophobic nature of the matrix allows the formulationto retain its shape and physical integrity. In the absence of thehydrophilic additive the active agent is very slowly and incompletelyreleased from the formulation. When the hydrophilic substance isincorporated into a formulation of the invention, water penetration intothe formulation is promoted, thereby providing sustained release of theactive agent. The hydrophilic additive absorbs water and causes theformulation to swell. Formulations of the invention containing ahydrophilic additive cause the active agent to be released morecompletely and over a more prolonged period of time.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical formulation in capsuleunit dosage form comprising a gelatin capsule containing a semi-solidmatrix, said semi-solid matrix comprising a pharmaceutically activeagent, a pharmaceutically acceptable hydrophobic carrier matrix and ahydrophilic substance capable of creating channels in the hydrophobiccarrier matrix thereby providing a sustained rate of release of theactive agent from the formulation.

DETAILED DESCRIPTION OF THE INVENTION

The concentrations described herein of the ingredients employed in aformulation of the invention are based only on the ingredients presentin the semi-solid matrix. Therefore, the total concentration of thesemi-solid matrix constitutes 100% of the total formulation, as theweight of the capsules are not considered when calculating thepercentages provided hereinafter.

The formulation of the present invention will contain a hydrophilicsubstance capable of creating channels in the hydrophobic carrier matrixthereby providing a sustained rate of release of the active agent fromthe formulation. The term "hydrophilic substance capable of creatingchannels in the hydrophobic carrier matrix", as defined herein,represents one or more substances which have an affinity for water andwhich tend to combine readily with water. Once this hydrophilicsubstance is incorporated in the present formulations the entry of waterinto the formulation is facilitated by creating diffusion channels intothe hydrophobic carrier matrix so as to dissolve the pharmaceuticallyactive agent and permit its release over a prolonged period of time.

The hydrophilic substance will be present in the formulation at aconcentration in the range of about 10% to about 40% by weight, morepreferably about 15% to about 30% by weight. Exemplary hydrophilicsubstances suitable for use herein include starch, microcrystallinecellulose, cellulose with sodium carboxymethylcellulose such as AvicelRC-591 (FMC Corporation), hydroxypropyl methylcellulose derivatives,such as Methocel K15M, from Dow Chemical Company, modified cellulosegums such as Ac-Di-Sol from FMC Corporation and natural mucilagenoussubstances such as powdered psyllium.

Any number of pharmaceutically active agents may be employed in theformulations of the present invention. These active agents may exist aseither solids or liquids at standard temperature and pressure. Exemplarypharmaceutically active agents suitable for use herein include, but arenot limited to, the cardiovascular drugs such as propranolol; thecentral nervous system compounds such as haloperidol; the non-steroidalantiinflammatory agents such as piroxicam, indomethacin, fenoprofen andibuprofen; the antidepressants such as fluoxetine and tomoxetine; andthe antibacterial agents such as cefaclor, amoxicillin, ampicillin andespecially cephalexin. Other pharmaceutically active agents capable oforal administration may also be used herein. The quantity of activeagent present in a formulation of the invention will be from about 0.1%to about 60% by weight, more preferably from about 15% to about 40% byweight.

A variety of pharmaceutically acceptable hydrophobic carrier matricesmay be employed in the formulation of the invention. The quantity ofhydrophobic carrier matrix present in a formulation of the inventionwill be in the range of about 30% to about 60% by weight, morepreferably about 40% to about 55% by weight. The hydrophobic carriermatrices employed herein are amphiphiles in which the molecule or ioncontains both hydrophilic and lipophilic portions. These matrices can bedefined by a numerical value based on the Hydrophile-Lipophile Balancesystem, called the HLB system. The HLB scale is a numerical scale,extending from 0 to approximately 50, where lower numbers denote morelipophilic and hydrophobic substances, and higher numbers denote morehydrophilic and lipophobic substances. The affinity of a compound forwater, or for oily substances, is determined and its HLB value isassigned experimentally. Tables of such values have been published andformulation chemists are aware of them. The HLB of the hydrophobiccarrier matrix employed in the present formulation will be in the rangeof about 1 to about 10. Suitable pharmaceutically acceptable hydrophobiccarriers include the glycerides and partial glycerides. The preferredcarriers are known under the trademark Gelucire, and are commerciallyavailable from Gattefosse Corporation, Hawthorne, N.Y. Gelucires areavailable with varying physical characteristics such as melting point,HLB and solubilities in various solvents. The preferred Gelucire isGelucire 46/07, a substance commonly employed in hard gelatin capsules.

The formulations of the present invention are prepared by procedureswell known to one of ordinary skill in the art. Typically, thepharmaceutically acceptable hydrophobic carrier matrix is melted, ifnecessary, to provide a flowable liquid thereby making it easier toobtain a homogeneous mixture. The active agent and hydrophilic substanceare next added to the liquid carrier, and the ingredients are combinedto provide a homogeneous mixture of the semi-solid matrix.

The semi-solid matrix is placed in capsules prior to administration tothe patient in need of treatment. Such capsules may be hard or soft,although semi-solid matrix technology is more routinely associated withhard capsules. The semi-solid matrix employed in the present formulationmay be filled into hard gelatin capsules using standard capsule fillingmachinery modified in that the conventional powder filling parts arereplaced with a semi-solid filling head. These filling heads are knownand readily available from a variety of commercial vendors.

The formulations of the present invention are believed to provideprolonged gastric retention by one or both of the following mechanisms.The formulations are composed of a hydrophilic substance which causesswelling of the hydrophobic carrier matrix, thereby prolonging theformulation's gastric residence and delaying the passage of theformulation past the pylorus into the intestinal tract. As such, theactive agent is released over a prolonged period of time. The presentformulation may also have bioadhesive properties, such that theformulation actually interacts with the mucous layer of the stomach.However, regardless of their mechanism of action, the presentformulations are not limited by any mode of operation.

The following Examples illustrate specific formulations comprehended bythe present invention, and methods for their preparation. The Examplesare not intended to be limiting to the scope of the invention in anyrespect and should not be so construed.

EXAMPLE 1

To 7.5 g (41.7% by weight) of molten Gelucire 46/07 heated on a 70° C.water bath was added 6.0 g (33.3% by weight) of cephalexin monohydrate,4.5 g (25% by weight) of Avicel RC-591. The mixture was stirred andadded to clear 000 hard gelatin capsules to provide filled capsulesweighing approximately 1.5 g each.

EXAMPLE 2

To 9.0 g (50% by weight) of molten Gelucire 46/07 at 70° C. was added6.0 g (33.3% by weight) of cephalexin monohydrate and 3.0 g (16.7% byweight) of powdered psyllium seed containing 85% husks.(40 mesh). Themixture was stirred until homogeneous and placed into size 000 hardgelatin capsules, each weighing 1.6 g following filling with themixture.

EXAMPLE 3

A mixture of 9.0 g (50.0% by weight) of molten Gelucire 46/07, 6.0 g(33.3% by weight) of cephalexin monohydrate and 3.0 g (16.7% by weight)of Methocel K15M was added to 000 hard gelatin capsules.

EXAMPLE 4

To 5.0 g (50% by weight) of molten Gelucire 46/07 at 70° C. was added3.0 g (30% by weight) of Avicel RC-591 and 2.0 g (20% by weight) of(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride(tomoxetine hydrochloride). The resulting mixture was stirred untilhomogeneous. The mixture was placed into size 0 capsules. The finalcapsules weighed approximately 300 mg each.

EXAMPLE 5

To 3.375 g (50% by weight) of molten Gelucire 46/07 under agitation wasadded 2.025 g (30% by weight) hydrochloride. The mixture was stirreduntil homogeneous. The mixture was placed into size 0 clear capsules,each filled capsule weighing about 225 mg, and an additional 15 mg oftomoxetine hydrochloride was added to each capsule.

The following procedure was used to determine the level of cephalexin inthe plasma of dogs following administration of a formulation of theinvention. Six fed dogs were orally administered one capsule each of thespecified formulation of the invention. Blood samples were taken fromthe dogs at about 0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0,14.0 and 24.0 hours after administration. The blood samples werecentrifuged and the plasma samples were frozen during storage. Thefrozen plasma samples were warmed to room temperature and 0.5 ml ofplasma was added to a microcentrifuge tube. To the plasma was added 0.5ml of 10% aqueous trichloroacetic acid (v/v) and the resulting mixturewas centrifuged for seven minutes. The supernatant was chromatographedover an HPLC silica gel column and compared to a reference standard.

A reference standard was prepared from plasma obtained from bloodsamples drawn from dogs just prior to administration with a formulationof the invention. This standard was prepared by adding 0.125 ml of anaqueous solution of cephalexin monohydrate and 0.125 ml of 20% aqueoustrichloroacetic acid (v/v) to 0.25 ml of plasma in a microcentrifugetube. The resulting mixture was centrifuged for seven minutes and thesupernatant was chromatographed on an HPLC column. The results of thistest are set forth below in Table I as the average of n trials.

                  TABLE I                                                         ______________________________________                                        Plasma Levels of Cephalexin in Dogs (μg/ml)                                Time After   Example No.                                                      Administration (hours)                                                                     1 (n = 3)   2 (n = 6)                                                                              3 (n = 3)                                   ______________________________________                                        0            0           0        0                                           0.5          0           0.22     0                                           1.0          0           1.52     0                                           1.5          0.24        2.80     0.71                                        2.0          0.75        4.06     2.04                                        3.0          2.88        6.98     4.54                                        4.0          6.40        9.00     7.19                                        6.0          12.60       11.67    9.02                                        8.0          15.88       11.00    8.35                                        10.0         15.40       10.02    8.22                                        12.0         11.33       8.60     7.39                                        14.0         8.16        7.98     6.05                                        24.0         1.67        3.50     0.58                                        ______________________________________                                    

A similar study was carried out with the formulation of Example 4described above. This study measured the plasma level of tomoxetinehydrochloride in dogs at various times following oral administration ofthe formulation. Each of three dogs was dosed with 60 mg of the activeagent and an average was obtained. The results of this study are setforth below in Table II.

                  TABLE II                                                        ______________________________________                                        Plasma Levels of Tomoxetine Hydrochloride                                                      Plasma Level                                                 Time After       of Active Agent                                              Administration (minutes)                                                                       in Dogs (μg/ml)                                           ______________________________________                                         30              0                                                             60              0.05                                                          90              0.10                                                         120              0.14                                                         180              0.41                                                         240              0.56                                                         360              0.80                                                         480              0.56                                                         600              0.37                                                         720              0.20                                                         840              0.12                                                         1440             0.02                                                         ______________________________________                                    

We claim:
 1. A pharmaceutical formulation in capsule unit dosage formcomprising a gelatin capsule containing a semi-solid matrix, saidsemi-solid matrix comprising a pharmaceutically active antidepressantagent, a pharmaceutically acceptable hydrophobic carrier matrix and ahydrophilic substance capable of creating channels in the hydrophobiccarrier matrix thereby providing a sustained rate of release of theactive agent from the formulation.
 2. The formulation of claim 1 whereinthe active agent is tomoxetine hydrochloride.